Method of controlling body temperature while reducing shivering

ABSTRACT

A method and apparatus for lowering the body temperature of a patient while reducing shivering by using a heat exchange device in combination with an α2-adrenoreceptor agonist, a non-opiod analgesic monoamine uptake inhibitor or neuropeptide that temporarily reduces shivering. The devices disclosed include a catheter having a heat exchange balloon thereon with heat exchange fluid circulating through the interior of the balloon. The heat exchange balloon is placed in the vasculature of a patient, and heat exchange fluid at a temperature other than the temperature of the blood in the vasculature is circulated through the interior of the balloon to add or remove heat from the blood of the patient. Various α2-adrenoreceptor agonistα2-adrenoreceptor agonists, non-opiod analgesic monoamine uptake inhibitors and neuropeptides are disclosed including dexmedetomidine, nefopam, neurotensin and anticonvulsant medications and pharmaceutically acceptable salts thereof. A control system for the control of the patient&#39;s temperature is disclosed for controlling the patient&#39;s temperature in conjunction with administering the α2-adrenoreceptor agonist, non-opiod analgesic monoamine uptake inhibitor or neuropeptide.

RELATED PATENT APPLICATION

This patent application is a continuation of U.S. patent applicationSer. No. 10/137,741 filed on May 2, 2002 and now issued as U.S. Pat. No.6,702,839, which is a continuation-in-part of U.S. patent applicationSer. No. 09/372,714 filed on Aug. 11, 1999 and now issued as U.S. Pat.No. 6,231,594.

INTRODUCTION

1. Technical Field

This invention relates to a method, apparatus and composition forselectively controlling the temperature of all or a portion of apatient's body by lowering, maintaining or raising the temperature of abody fluid or tissue to affect the temperature of all or part of thepatient's body, while reducing shivering that typically accompanies suchtemperature control. More particularly, the invention relates to a heatexchange device in combination with an anti-shivering mechanism tocontrol the temperature of all of a portion of a patient's body whilereducing shivering. The invention also relates to novel compositionsthat are useful for reducing shivering.

2. Background

The “set point temperature” is the temperature that the body attempts tomaintain through the thermoregulatory responses. Under ordinarycircumstances, thermoregulatory mechanisms within the human body whichinclude sweating and vasodilation to enhance heat loss, arterio venous(“AV”) shunting and vasoconstriction to enhance retaining heat, andshivering to enhance increased generation of body heat, serve tomaintain the body at a near constant set point temperature of about 37°C. (98.6° F.), often referred to as “normothermic”. However, sometimesthe body sets a different set point temperature, for example a patientwith a fever has an elevated set point temperature, and these mechanismscan serve to maintain an elevated temperature. In the case of a fever,the set point temperature can be higher than normothermic.

There is a temperature slightly below the set point temperature wherethe body senses that the body temperature is too low and begins toshiver. This temperature is sometimes referred to as the shiveringthreshold. As with the set point temperature, the shivering threshold isnot an absolute temperature but varies between individuals and withinthe same individual depending on his or her condition.

As a result of the thermoregulatory mechanisms, any heat lost to theenvironment is precisely balanced by heat produced within the body.Accordingly, attempts to control the body temperature below the setpoint temperature often produce shivering in the patient, as this is themain method of generating additional metabolic heat. Shivering canincrease heat production by 200–500% and thus presents a seriousobstacle when attempts are made to reduce a patient's body temperature.

The thermoregulatory mechanisms provide a formidable defense whenattempts are made to lower the body temperature below the set pointtemperature, for example, when one attempts to induce an artificiallylow body temperature (a condition known as hypothermia) by lowering thenormothermic 37° C. to a lower temperature state or when one attempts tomaintain normothermia by lowering an elevated body temperature tonormothermic 37° C. Since there are numerous therapeutic reasons forboth inducing hypothermia or inducing normothermia in a patientsuffering from an elevated temperature, the thermoregulatory mechanismsmust be taken into consideration when designing a therapeutic regimenfor controlling the temperature of all or a portion of a patient's body.Indeed, when the patient has a set point temperature that is abovenormothermic, for example when the patient has a fever, the shiveringthreshold may actually be above normothermic as well, and thus even anattempt to maintain a patient's temperature to normothermia may resultin shivering. In addition, even when the thermoregulatory mechanismshave been overcome, the body temperature may continue to drop, possiblybelow the desired threshold. This “overshooting” phenomenon can lead tocomplications. Accordingly, any therapeutic regimen for controlling bodytemperature preferably does so at a carefully monitored and controlledrate.

It has also been found that in rewarming a patient, either aftertherapeutic hypothermia or a patient suffering from accidentalhypothermia, a very gradual and controlled rewarming rate is desirable.The dramatic generation of metabolic heat due to shivering, particularlyin addition to heat added by other means, can result in rapid anduncontrolled rewarming. Therefore therapeutic rewarming at a carefullymonitored and controlled rate also requires control over shivering.

Hypothermia may be induced to minimize damage to the brain when apatient has suffered a head injury or stroke, or to minimize damage toheart and brain tissue when a patient has undergone cardiac arrest. Itmay sometimes also be desirable to induce hypothermia during surgery,especially neurosurgery, once again to minimize tissue damage.

Early techniques involved application of cold to the skin surface orcooling the inspired air, alone or in combination with a compound toinhibit the thermoregulatory center such as chlorpromazine (Ripstein, etal., Surgery (35)1:98–103 (1954)). More recently, in situ bloodtemperature modification using a heat exchange catheter was described inGinsburg, U.S. Pat. No. 5,486,208 and Ginsburg, WP 98/268831, thedisclosures of which are incorporated herein by reference. This in situprocedure lowers the body temperature much faster and maintains thetemperature at that lower level more precisely than the cooled skinsurface or cooled breathing air methods described above.

There are also drugs which are capable of assisting in lowering bodytemperature. However, many require toxic doses in order to achieve thedesired hypothermic state. Temperature lowering was also allegedlyachieved with chlorpromazine, when administered in combination with arefrigeration blanket (Ripstein, et al, supra), and when administeredalone (Chai, et al., Br. J. Pharmac. 57:43–49 (1976)). However, in boththese instances, temperature variation after the chlorpromazine wasadministered was achieved by external cooling or exposure alone andwithout any significant control of the degree or rate of body cooling.More recently, hypothermia was allegedly induced in rats with acombination of a κ opioid receptor agonist and a dopamine receptorblocker or agonist (Adler, et al., U.S. Pat. No. 4,758,562). It has beenshown that the α₂-adrenoreceptor agonists dexmedetomidine and clonidineare able to lower the shivering threshold (Talke, et al., Anesthesiology87(4):835–841, 1997). In this study, patients at a normal temperaturewere warmed until sweating then cooled until shivering occurred, as theα₂-adrenoreceptor agonist was administered. Evaluation of the ability ofthese agonists and a novel agonist to reduce core temperature were laterdescribed in Millan, et al., The Journal of Pharmacology andExperimental Therapeutics 295(3):1192–1205, 2000. However, in both thesestudies, as with chlorpromazine, temperature variation after theα₂-adrenoreceptor agonist was administered was achieved with only minorcontrol of the degree or rate of body cooling.

However, in spite of these advances, there continues to be a need todevelop a method of safely and temporarily inactivating the shiveringresponse while inducing hypothermia or otherwise reducing the body'stemperature below its set point temperature for an extended period oftime, or while gently and slowly raising the body's temperature from ahypothermic state.

SUMMARY

The present invention pertains to a method for controlling thetemperature of all or a portion of a patient's body to a temperaturebelow its set point temperature, while reducing shivering, comprisingthe steps of: (a) sensing the temperature of all or a portion of thepatient's body; (b) generating a signal based upon the sensedtemperature; (c) controlling the temperature of all or a portion of thepatient's body based upon the signal; and (d) administering an agentselected from the group consisting of α2-adrenoreceptor agonists,non-opiod analgesic monoamine uptake inhibitors ,neuropeptides, nefopamand an anticonvulsant drug to the patient.

In many ways, the muscular activity of shivering, which is a highfrequency, random-like muscular contraction that is not coordinated toproduce intentional motion, is similar to the high frequency,random-like muscular activity exhibited during some seizures,particularly tonic-clonic seizures. The anticonvulsant medications thatact to inhibit the seizures also may act to inhibit the shivering of apatient which is cooled below the shivering threshold. There may also bea more generalized pharmacological inhibition of the thermoregulatoryresponse of the patient which is helpful when the patient's temperatureis controlled by an endovascular cooling system as described below andnot by the natural thermoregulatory mechanisms of the body.

The anticonvulsant drugs includes any of the pharmaceutically acceptableanticonvulsant medications including without limitation currently knownanticonvulsant drugs which may be useable in accordance with thisinvention include but are not limited to hydantoins (e.g., phenytoin(Dilantin)), anticonvulsant barbiturates (e.g., phenobarbital),deoxybarbiturates (e.g., primidone), iminostilbenes (e.g., carbamazepine(Tegretol)), succinimides (e.g., ethosuximide, methsuximide,phensuximide), oxazolidinediones (e.g., trimethadione, paramethadione),benzodiazepines (e.g., diazepam, chlordiazeppoxide, oxazepam,chlorazepate, nitrazepam, clonazepam, lorazepam), acetylureas (e.g.,phenacemide, pheneturide) and sulfonamides and carbonic anhydraseinhibitors (e.g., acetazolamide, sulthiame, bromide). ,), gabapetin,lamotrigine, primidone, and valproate or pro-drugs or metabolicprecursors of any such anticonvulsant agents. Because of its method ofadministration, dosage and availability, phenytoin is described indetail below. That does not preclude the use of the other drugs in thisinvention. Furthermore, it is also known that the effectiveness of theanti-shivering drugs may be greatly enhanced by the application of awarming blanket at the times when the patient is at or below what wouldbe the patient's shivering threshold if the drugs had not beenadministered. Thus any of the methods described below may include thestep of placing a warming blanket over the surface of the patient at thesame time as administering the anti-shivering drugs.

In one embodiment of the invention, the aforementioned method isutilized to lower a patient's body temperature below its set pointtemperature while reducing shivering.

In yet another embodiment of the invention, the aforementioned method isutilized to raise a patient's body temperature from an initialtemperature below the set point temperature while reducing shivering.

Another embodiment of this invention is to utilize the aforementionedmethod to raise a patient's body temperature at a predetermined ratewhile reducing shivering.

Still another embodiment of the invention is to utilize theaforementioned method to slowly and controllably rewarm a hypothermicpatient from a temperature below the set point temperature towardnormothermia.

Another embodiment of the invention is to utilize the aforementionedmethod to maintain a patient's body temperature at a stable temperaturebelow the set point temperature while reducing shivering.

Yet another embodiment of the invention comprises controlling apatient's body temperature by placing a heat exchange device having aheat exchange region into the vascular system of the patient andcontrolling the temperature of the heat exchange region for a sufficienttime to affect the temperature of all or a portion of the patient'sbody, while administering an agent selected from the group consisting ofα2-adrenoreceptor agonists, non-opiod analgesic monoamine uptakeinhibitors, neuropeptides, nefopam and an anticonvulsant drug to thepatient.

Still another embodiment of the invention is a method of controlling apatient's body temperature by administering an agent selected from thegroup consisting of α2-adrenoreceptor agonists, non-opiod analgesicmonoamine uptake inhibitors, neuropeptides, nefopam and ananticonvulsant drug to the patient while using a heat exchange devicethat is a catheter and the heat exchange region comprises a balloon onthe catheter, the temperature of the balloon being controlled by thecirculation of a heat exchange fluid through the interior of theballoon. The catheter may have a shaft for the circulation of heatexchange fluid, where fluid circulates through the shaft and through theinterior of the balloon.

Another embodiment of the invention relates to controlling thetemperature of all or a portion of a patient's body by using a heatexchange device in combination with an agent selected from the groupconsisting of α2-adrenoreceptor agonists, non-opiod analgesic monoamineuptake inhibitors, neuropeptides, nefopam and an anticonvulsant drug orpharmaceutically acceptable salt thereof.

Yet another embodiment of the invention is a method of controlling thetemperature of a patient by using a heat exchange device andadministering dexmedetomidine.

Yet another embodiment of the invention is a method of controlling thetemperature of a patient by using a heat exchange device andadministering nefopam.

Yet another embodiment of the invention is a method of controlling thetemperature of a patient by using a heat exchange device andadministering neurotensin.

In yet anther embodiment of the invention, a method is provided forcontrolling the temperature of a patient by using a heat exchange deviceand administering an anticonvulsant drug.

In yet anther embodiment of the invention, a method is provided forcontrolling the temperature of a patient by using a heat exchange deviceand administering an intravenous dose of fosphenytoin.

The present invention further comprises a method of controlling apatient's body temperature below its set point temperature with aninternal heat exchange device, while simultaneously inactivating theshivering response of the patient.

One embodiment of the invention pertains to a method of controlling thetemperature of a patient below the set point temperature comprising thesteps of: (a) employing internal in vivo core temperature regulation;and (b) administering an α2-adrenoreceptor agonist.

One embodiment of the invention pertains to a method of controlling thetemperature of a patient below the set point temperature comprising thesteps of: (a) employing internal in vivo core temperature regulation;and (b) administering of an anticonvulsant drug.

One embodiment of the invention pertains to a method of controlling thetemperature of a patient below the set point temperature comprising thesteps of: (a) employing internal in vivo core temperature regulation;(b) placing a warming blanket over the surface of the patient, and (c)administering an anticonvulsant drug.

In another embodiment of the invention, the step of employing internalin vivo core temperature regulation comprises placing a heat exchangedevice in the blood vessels of the patient, where the heat exchangedevice has a heat exchange region which is in contact with the flowingblood of the patient; and controlling the temperature of the heatexchange region for a sufficient time to affect the temperature of thepatient, while administering an agent selected from the group consistingof α2-adrenoreceptor agonists, non-opiod analgesic monoamine uptakeinhibitors, neuropeptides, nefopam and an anticonvulsant drug to thepatient.

Yet another embodiment of the invention is a kit for reducing thetemperature of a patient comprising a heat exchange device and an agentselected from the group consisting of α2-adrenoreceptor agonists,non-opiod analgesic monoamine uptake inhibitors and neuropeptides. Thekit may further comprising a set of instructions for use of the heatexchange device and/or administration of the agent. The kit may alsocomprise a control system which measures patient body temperature andcontrols the heat exchange device in response to the body temperature.

These and other embodiments of the invention are achieved by the method,apparatus, kit and composition described herein where a patient's bodytemperature is lowered, such as by inducing hypothermia, utilizing aheat exchange device in combination with an agent selected from thegroup consisting of α2-adrenoreceptor agonists, non-opiod analgesicmonoamine uptake inhibitors, neuropeptides, nefopam and ananticonvulsant drug. Such device can comprise an elongate flexiblecatheter having a heat exchanger that operates to exchange heat betweentissue, blood or other body fluid that flows in or is positioned in heatexchanging proximity thereto.

Further aspects and details of the present invention will becomeapparent to those of skill in the relevant art upon reading andunderstanding of the detailed description of preferred embodiments setforth here below. Each of the embodiments disclosed below may beconsidered individually or in combination with any of the othervariations and aspects of the invention.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 depicts a heat exchange device inserted percutaneously into ablood vessel of a patient.

FIG. 2 illustrates a heat exchange device having a heat exchange regionpositioned within the left common carotid artery.

FIG. 3 depicts a heat exchange catheter having a heat exchange balloonand a plurality of heat transfer fins.

FIG. 4 is a cross-sectional view of the distal end of the catheter takenalong line 4—4 of FIG. 3.

FIG. 5 is a cross-sectional view of the central section of the cathetertaken along line 5—5 of FIG. 3.

FIG. 6 is a cross-sectional view of the proximal end of the cathetertaken along line 6—6 of FIG. 3.

FIG. 7 illustrates an alternative construction of a heat exchangecatheter.

FIG. 8 is a cross-sectional view of the distal end of the catheter takenalong line 8—8 of FIG. 7.

FIG. 9 is a cross-sectional view of a portion of the central section ofthe catheter taken along line 9—9 of FIG. 7.

FIG. 10 is a cross-sectional view of another portion of the centralsection of the catheter taken along line 10—10 of FIG. 7.

FIG. 11 is a cross-sectional view of the proximal end of the cathetertaken along line 11—11 of FIG. 7.

FIG. 12 is a cross-sectional view of the proximal shaft of the cathetertaken along line 12—12 of FIG. 7.

FIG. 13 depicts another embodiment a heat exchange catheter, asassembled.

FIG. 14 shows the shaft member of the catheter assembly of FIG. 13.

FIG. 15 illustrates the balloon configuration of the catheter assemblyof FIG. 13.

FIG. 16 is a cross-sectional view of the balloon of FIG. 15 taken alongline 16—16.

FIG. 17 is a cross-sectional view of the shaft of FIG. 13 taken alongline 17—17.

FIG. 18 is a cross-sectional view of the catheter of FIG. 13 taken alongline 18—18.

FIG. 19 is a view of a portion of the catheter of FIG. 13 illustratingoutflow of heat exchange fluid.

FIG. 20 is a cross-sectional view of the catheter of FIG. 13 taken alongline 20—20.

FIG. 21 is a view of a portion of the catheter of FIG. 13 illustratinginflow of heat exchange fluid.

FIG. 22 is a cross-sectional view of the catheter of FIG. 13 taken alongline 22—22.

FIG. 23 is a flow chart illustrating a preferred method of theinvention.

FIG. 24 is a front view of control system useful in the methods of theinvention.

FIG. 25 illustrates a control system in operation.

DETAILED DESCRIPTION

The present invention comprises a method of controlling a patient's bodytemperature to a temperature below its set point temperature, such asinducing hypothermia, while simultaneously combating thermoregulatoryresponses of the patient. More specifically, the invention provides fora method, apparatus, kit and composition for reducing the body'stemperature below its set point temperature for an extended period oftime while temporarily inactivating the shivering response.

Inactivation of the thermoregulatory mechanisms allows one to lower thebody temperature below the set point temperature while reducingshivering in the patient. The methods described herein inactivate thethermoregulatory response by means of an agent selected from the groupconsisting of α2-adrenoreceptor agonists, non-opiod analgesic monoamineuptake inhibitors, neuropeptides, nefopam, and an anticonvulsant drugwhich functions as an anti-shivering mechanism, and which can beadministered prior to, simultaneous with, or subsequent to initiation ofthe temperature lowering step.

Before describing detailed embodiments of the invention, it will beuseful to set forth definitions that are used in describing theinvention. The definitions set forth apply only to the terms as they areused in this patent and may not be applicable to the same terms as usedelsewhere, for example in scientific literature or other patents orapplications including other applications by these inventors or assignedto common owners. Additionally, when examples are given, they areintended to be exemplary only and not to be restrictive. For example,when an example is said to “include” a specific feature, that isintended to imply that it may have that feature but not that suchexamples are limited to those that include that feature.

The term “set point temperature” is used herein to refer to thetemperature that the body attempts to maintain through thethermoregulatory responses. The set point temperature can vary bothbetween individuals and within the same individual at different times.For example, in a healthy individual, the set point temperature isusually about 37° C. However, the set point temperature can be changed,for example when an individual is ill and the body develops a fever. Inthat instance the thermoregulatory system actually works to maintain ahigher than normal body temperature. Thus, in such circumstances the setpoint temperature can be higher than 37° C.

As used herein, the term “lowered temperature state” is intended to meana state where the temperature of all or a portion of a patient's bodyhas been reduced to a temperature below the set point temperature. Theterm “lowered temperature state” includes, for example, the lowering ofan elevated body temperature to normothermic (about 37° C.). Here, theset point temperature is a fever and the body temperature is reduced to37° C., a temperature below the fevered set point temperature. Moretypically, the term “reduced temperature state” refers to a “hypothermicstate”, which can occur when the normal body temperature of 37° C. isreduced to a lower temperature, i.e., the set point temperature is anormal 37° C. state and the body temperature is reduced to below 37° C.Typically, hypothermia may be induced by lowering the patient'stemperature until it is about 32° C. It is understood, however, thatthese temperature values provide a useful basis for discussion butdefinitions vary widely in the medical literature.

As used herein the term “normothermic” is intended to mean a temperatureof about 37° C. (98.6° F.).

As used herein, the term “shivering” is intended to mean theuncontrolled muscle movement that an animal typically experiences whencold that does not result in controlled and coordinated movement of theorganism, and includes, for example, trembling and quaking. Moreprecisely, the term is used to mean the, trembling or quaking that ananimal experiences when it's body temperature falls to a certaintemperature below its set point temperature, said “certain temperature”sometimes being referred to as the “shivering threshold”.

As used herein, the term “reduce” as it pertains to shivering isintended to include minimizing shivering to a noticeable degree,eliminating shivering in its entirety and preventing shivering fromstarting.

As used herein, the term “patient” will typically be mammalian, and mostcommonly a human. As such, the term “therapeutically effective amount”is intended to mean a dosage sufficient to reduce shivering in thepatient being treated, and will vary depending upon various factors suchas the patient species, the particular drug used, e.g theα2-adrenoreceptor agonist, non-opiod analgesic monoamine uptakeinhibitor, neuropeptide, nefopam or anticonvulsant drugused, thepatient's age, weight and other characteristics, including anyindividual sensitivity.

In general, the method of the invention relates to controlling thetemperature of all or a portion of a patient's body to a temperaturebelow its set point temperature, while reducing shivering. One exampleof the method of the invention comprises the steps of: (a) sensing thetemperature of all or a portion of the patient's body; (b) generating asignal based upon the sensed temperature; (c) controlling thetemperature of all or a portion of the patient's body based upon thesignal; and (d) reducing or eliminating shivering by placing a warmingblanket over the surface of the patient and administering an agentselected from the group consisting of α2-adrenoreceptor agonists,non-opiod analgesic monoamine uptake inhibitors, neuropeptides, nefopam,and an anticonvulsant drug to the patient.

As used herein, the term “controlling the temperature” is intended toinclude lowering the temperature below the set point temperature,raising the temperature from an initial temperature below the set pointtemperature, raising the temperature at a predetermined rate orincrease, and maintaining the temperature at a stable temperature belowthe set point temperature. Such stable temperature can be, for example,normothermia.

An example of one such method comprises the steps of: (a) positioning aheat exchange device within the patient and in heat exchanging proximityto body fluid such as blood; (b) utilizing the device to lower thetemperature of said body fluid to a sufficient degree and for asufficient duration to alter the temperature of said body; and (c)reducing or eliminating shivering by placing a warming blanket over thesurface of the patient and administering an agent selected from thegroup consisting of α2-adrenoreceptor agonists, non-opiod analgesicmonoamine uptake inhibitors, neuropeptides, nefopam, and ananticonvulsant drug to the patient. As used herein, the term “utilize”is intended to include, for example, activating the device, adjustingthe thermal output of the device and deactivating the device. Thepositioning step can involve, for example, placing a heat exchangedevice having a heat exchange region into the vascular system of thepatient. The temperature of the heat exchange region is then controlledfor a sufficient time to affect the temperature of the patient.

Although the methods of the invention may be used to cool the entirepatient's body, they may be useful in cooling a specified portion of apatient's body. For example, the methods of the invention may cool thebrain or a portion thereof to deter neural damage following a stroke orother insult (e.g., period of ischemia, period of hypoxia, hemorrhage,trauma, etc.). In this manner, the heat exchange device would bepositioned in a blood vessel which leads to the brain, such as the rightcommon carotid artery, left common carotid artery, innominate artery,right internal carotid artery, left internal carotid artery, and soforth. Alternatively, the heat exchange device may be positioned in alarge vein such as the inferior vena cava and heat removed from theblood for a sufficient length of time to cool the entire body and thuscool the neural tissue, such as the brain and spinal cord, as well.

It may also be desirable to cool the entire patient's body such as afebrile patient. For example, in stroke patients who have becomefebrile, it may be therapeutically desirable to reduce the body'stemperature to normothermic. In particular, the methods of the inventionfind utility in treating patients that have suffered a stroke, sincestoke patients often develop a fever. Even a slight fever in these casesis correlated with much worse outcomes than in patients who do not havea fever. In such cases, it is advantageous to maintain the patient atnormothermia. However, since patient's with a fever often have their setpoint reset to a temperature above normothermia, even reducing thepatient's temperature to normal in those cases may trigger shiveringwith the attendant problems.

The methods of the invention serve to lower the temperature to atemperature below its set point temperature, while simultaneouslyinactivating the thermoregulatory response by means of an anti-shiveringmechanism. The order of the steps of the method can be conducted severalways in that the α2-adrenoreceptor agonist, non-opiod analgesicmonoamine uptake inhibitor, neuropeptide, nefopam and an anticonvulsantdrug can be administered prior to, simultaneous with, or subsequent toinitiation of the temperature lowering step. In this manner, theα2-adrenoreceptor agonist, non-opiod analgesic monoamine uptakeinhibitor or neuropeptide can be administered to the patient: prior tocontrolling the body temperature, for example, prior to positioning aheat exchange device; after positioning the device but beforeutilization; simultaneous with the utilization step (b); or subsequentto the utilization step.

Several acceptable methods are illustrated in FIG. 23 in the form of aflow chart. For sequential administration routes, the α2-adrenoreceptoragonist, non-opiod analgesic monoamine uptake inhibitor, neuropeptides,nefopam and an anticonvulsant drug can be administered beforepositioning the heat exchange device (200), after the device has beenpositioned (202), after the device has been activated (204), or afterthe device has been deactivated (206), the latter being useful if it isdesired to administer the anti-shivering mechanism after the body hasalready been cooled to the desired temperature. For simultaneousadministration routes, the α2-adrenoreceptor agonist, non-opiodanalgesic monoamine uptake inhibitor neuropeptide, nefopam, and ananticonvulsant drug can be administered simultaneously with thepositioning of the heat exchange device (208) or while the device isactivated (210). The invention also contemplates administering theα2-adrenoreceptor agonist, non-opiod analgesic monoamine uptakeinhibitor, neuropeptides, nefopam and an anticonvulsant drug in anycombination of the aforementioned sequential and simultaneous routes.

In another aspect of the invention, a method of controlling thetemperature of a patient below the set point temperature comprises thesteps of: (a) employing internal in vivo core temperature regulation;and (b) administration of an agent selected from the group consisting ofα2-adrenoreceptor agonists, non-opiod analgesic monoamine uptakeinhibitors, neuropeptides, nefopam and an anticonvulsant drug. One meansof employing internal in vivo core temperature regulation comprisesplacing a heat exchange device in the blood vessels of the patient,where the heat exchange device has a heat exchange region that is incontact with the flowing blood of the patient. The temperature of theheat exchange region can then be controlled for a sufficient time toaffect the temperature of the patient. The heat exchange device may be acatheter having a shaft for the circulation of heat exchange fluidtherein. The heat exchange region can be a balloon; and the temperatureof the heat exchange region is controlled by circulation of heatexchange fluid through the shaft and the interior of said balloon.

As noted above, the cooling aspect of the invention operates to cool theentire patient's body to lower the patient's body temperature, or tocool a portion of the patient's body, for example, to minimize damage toa particular body tissue.

In a preferred method of the invention, the body temperature is loweredby cooling a body fluid in situ for a sufficient length of time to lowerthe temperature by the desired amount, while reducing patient shiveringthat typically accompanies such cooling by placing a warming blanketover the surface of the patient and administering an α2-adrenoreceptoragonist, non-opiod analgesic monoamine uptake inhibitor, neuropeptides,nefopam and an anticonvulsant drug. Typical body fluids include, blood,cerebral spinal fluid, peritoneal fluid or the like, but will typicallybe blood. In addition, the methods of the invention will generallyresult in in situ cooling of target body tissues and organs, either bycooling body fluid directed to the tissue, as in cooling the brain bycooling blood flowing through the carotid artery, or by cooling thewhole body which results in cooling the target tissue. Typical bodytissues and organs that may be the target tissue include, neural tissue,brain, heart, spinal cord tissue, kidney, liver and the like, but willtypically be the heart and the brain.

The heat exchange device itself may have a temperature within the rangeof 0 to 42° C. By controlling the temperature of the portion of thedevice that is in heat exchanging proximity to the body fluid so that atemperature differential (ΔT) exists between the heat exchange deviceand the body fluid, heat is transferred between the device and the bodyfluid. For example, when the body temperature is lowered by coolingblood, the heat exchange device is positioned within a blood vessel andmaintained with a temperature below that of the blood flowing past theheat exchange device so that heat is transferred between the device andblood flowing through the vessel. Blood flows in heat transfer proximityto the heat exchange device and is cooled. By continuing to cool fluidflowing past the heat exchanger in sufficient volume and for asufficient length of time, the temperature of the patient is reduced.The methods of the invention are suited to lower the body temperature ofa patient by as much as 9° C. It is not expected to reduce the patient'sbody temperature to less than 28° C., and preferably not lower than 32°C.

Another important aspect of the instant invention is that thetemperature of the patient's body or portion thereof can be reducedcontrollably, thus avoiding the problems associated with cooling apatient too rapidly, or below a desired temperature. Likewise, when ahypothermic patient is warmed, the combination of an internal heatexchange device controlled by feedback with the anti-shivering agentthat reduces the body's shivering and thus allow more precise controlover the patient's temperature, permits a more gradual and gentlewarming of the patient. It will be readily seen that if a patient ismaintained at a reduced temperature below the set point temperature andparticularly below the shivering threshold, the administration of theanti-shivering agent in combination with feed-back controlled in vivoheat exchange permits a more effective temperature control of thepatient. In particular, when inducing hypothermia, a target tissue canbe cooled to the desired temperature and that temperature maintained bycontrolling the heat exchange device. This is shown schematically inFIG. 23, where feedback information is obtained from the patient, forexample, the patient's temperature is measured (either the temperatureof the entire body, the target tissue or fluid), and that feedbackinformation is used in a feedback system (212) to continually control oradjust the output of the heat exchange device. In this manner, thefeedback system may be used to achieve or maintain, for example apre-determined body or body fluid temperature, a pre-determined heatexchange device temperature or a pre-determined ΔT. This is optional,however. The methods of the invention are well suited for use where thedevice may operate in a simple on-off mode. That is, it may operate atfull power until deactivated (214) or where the device is activated,adjusted one or more times during its operation (216) and thendeactivated (218). Feedback information can also be obtained from thepatient regarding the amount of shivering being experienced and thisfeedback system (220) can be used to continually control or adjust theadministration of the anti-shivering agent.

Generally the methods of the invention will involve affecting thetemperature of the entire body, but different regions may becontrollably maintained at temperatures different from each other, forexample, by controlling different heat exchange devices at differentlocations with the patient's body.

In one embodiment of the invention, the heat exchange device ispositioned within the patient, preferably intravascularly. For example,the heat exchange device, such as a catheter, is inserted through apuncture or incision into a fluid containing portion of the patient'sbody, for example, percutaneously into a blood vessel. An internallypositioned device, i.e., core cooling, is advantageous as it circumventsvasoconstriction. Accordingly, in one embodiment of the invention, amethod of controlling a mammalian patient's temperature below thepatient's set point temperature, while inhibiting the patient'sthermoregulatory responses, comprises the steps of (a) positioning aheat exchange device in a blood vessel, for example a blood vesselleading to the vena cava or brain; (b) utilizing the device to decreasethe temperature of blood which passes in heat exchanging proximity tothe heat exchange device; and (c) administering an agent selected fromthe group consisting of α2-adrenoreceptor agonists, non-opiod analgesicmonoamine uptake inhibitors, neuropeptides, nefopam and ananticonvulsant drug to the patient.

The heat exchange device can have the configuration of a number ofmedical devices that are well known in the art. Although a catheter ispreferred, it is understood that any other suitable means of cooling thebody and/or target fluid or tissue is suitable for use in the instantinvention, and that the particular catheter configurations describedherein are intended to be exemplary and not limiting in any manner. Thepreferred heat exchange mechanism involves heat exchanger in contactwith a body fluid or tissue on its external surface, the heat exchangerbeing chilled or heated on its internal surface by circulation of achilled fluid which is preferably sterile saline or other biocompatiblefluid having appropriate heat transfer characteristics.

In one embodiment of the invention, a method of controlling a patient'stemperature comprises utilizing a heat exchange device which is acatheter. In addition, an anti-shivering agent is administered to thepatient to reduce shivering. A suitable catheter comprises an elongateflexible catheter having a heat exchanger which is capable of exchangingheat between blood or other body fluid which flow in heat exchangingproximity thereto. For example, a catheter having a heat exchanger orheat exchange region which may be, for example, a balloon with fins, isinserted through a puncture or incision into a fluid containing portionof the patients body, for example, a blood vessel. The temperature ofthe balloon is controlled by the circulation of a heat exchange fluidthrough the interior of the balloon. Blood flows in heat transferproximity past the heat exchanger. Heat exchange proximity requiressufficient proximity for effective heat exchange to occur and depends onsuch factors as the chemical and physical make-up of the blood, the rateof flow past the heat exchange surface, the pattern of blood flow pastthe heat exchanger, (laminar flow, turbulent flow, and the like), thedifference in temperature between the heat exchange surface and theblood, the material of which the heat exchange surface is made, and theproximity between the heat exchange surface and the blood. By continuingto cool fluid flowing in heat transfer proximity for a sufficient lengthof time, the body temperature of the patient is altered.

Anti-shivering Mechanism

As used herein, the term “anti-shivering mechanism” is intended to meanthe administration of an anti-shivering agent selected from the groupconsisting of α2-adrenoreceptor agonists, non-opiod analgesic monoamineuptake inhibitors , neuropeptides, nefopam and an anticonvulsant drug toa patient.

As used herein, the terms “α2-adrenoreceptor agonist”, “non-opiodanalgesic monoamine uptake inhibitor” and “neuropeptide” are intended tomean any biologically active agent or drug or combination of agents ordrugs within that class, that is administered to a patient for thepurpose of reducing shivering. The term is also intended to includepharmaceutically acceptable salts or variants of such agents whichretain the biological effectiveness of the agents themselves. Such saltsare often preferred as the salt form may have better solubility,increased duration of action, and so forth. Suitable salts are wellknown to those of skill in the art and may include the hydrochloride,methanesulfonate, mesylate, maleate, decanoate, enanthate, succinate,lactate, sulfate, and quaternary ammonium salts. Likewise, nefopam, andanticonvulsant drugs are intended to refer to those drugs, acceptablesalts, and other prodructs that may be useful to enhance administrationof the drug. For example, the intravenous administration of phenytoin isgenerally accomplished by adminstration of fosphenytoin which is aprodrug which is metaboloized into its active metabolite, phenytoin.

The α2-adrenoreceptor agonists suitable for use in the methods of theinvention, include by way of illustration and not limitation,dexmedetomidine; detomidine; medetomidine; clonidine; bromonidine;tizanidine; mivazerol; guanfacine; oxymetazonline;(R)-(−)-3′-(2-amino-1-hydroxyethyl) -4′-fluoro-methanesulfoanilide;2-[(5-methylbenz-1-ox-4-azin-6-yl)imino]imidazoline;5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine;5,6,7,8-tetrahydro-6-(2-propenyl)-4H-thiazolo[4,5-d]azepin-2-amine;6-ethyl-5,6,7,8-tetrahydro-4H-oxaazolo [4,5-d]azepin-2-amine;5,6-dihydroxyl-1,2,3,4-tetrahydro-1-naphyl-imidazoline; andpharmaceutically acceptable salts thereof.

The non-opiod analgesic monoamine uptake inhibitors suitable for use inthe methods of the invention, include by way of illustration and notlimitation, nefopam; tramadol; and pharmaceutically acceptable saltsthereof.

The neuropeptides suitable for use in the methods of the invention,include by way of illustration and not limitation, neurotensin;neurotensin analogs; bombesin; neuromedin; dermorphin; D-ala-deltorphin;and pharmaceutically acceptable variants thereof.

In most cases, however, when administered alone, a high dosage may berequired to achieve a desired temperature drop. In the instantinvention, the reduced temperature state is induced by a heat exchangedevice, such as a cooling catheter, while the anti-shivering agent isused to overcome shivering. Several agents from different classes mayalso be administered in combination, for example an α2-adrenoreceptoragonist may be administered in combination with a neuropeptide. In thismanner, small non-toxic dosages can be administered to achieve thedesired anti-shivering results. Accordingly, the suitability of ananti-shivering agent for use in the methods described herein dependsupon its ability to suppress the thermoregulatory mechanisms to reduceshivering during cooling and thereafter while the patient is maintainedat a temperature that would otherwise produce shivering.

As noted above, pharmaceutically acceptable salts of theα2-adrenoreceptor agonist are also well suited for use in the methods ofthe invention. These include dexmedetomidine hydrochloride, and soforth. Pharmaceutically acceptable salts of the non-opiod analgesicmonoamine uptake inhibitors are also well suited for use in the methodsof the invention as are pharmaceutically acceptable variants of theneuropeptides.

Typically, the anti-shivering agent or pharmaceutically acceptable saltor variant thereof will be administered in combination with apharmaceutically acceptable carrier.

A particularly well-suited α2-adrenoreceptor agonist is dexmedetomidineand its salt, dexmedetomidine hydrochloride (sold by Abbott Laboratoriesunder the mark Precedx™). Exposure to temperature extremes is oftenassociated with increases in circulating catecholamine concentrations.Dexmedetomidine is of particular interest since it acts as ananti-shivering agent, as well as acting to counter the surge incatecholamine levels that can occur when a patient's body temperaturedrops below its set point temperature. In addition, dexmedetomidine, aswell as nefopam and neurotensin, causes minimal depression of therespiratory drive in patients, as opposed to other agents such asopiods.

The administration of anticonvulsant medications in the shiveringsuppression context may generally be accomplished by the intravenousadministration of an anticonvulsant pro-drug, such as fosphenytoin, atleast 15 minutes before the shivering suppression is desired.Anticonvulsant pro-drugs form active metabolites within the body thatprovide the desired anticonvulsant effects. For example, fosphenytoin ismetabolized to phenytoin with the resultant anti-shivering propertiesbeing exhibited when a sufficient level of the phenytoin metabolite isdeveloped in the body. A dosage of fosphenytoin that has been found tobe effective is set out below.

Dosage of Anti-shivering Agents

A therapeutically effective amount of the anti-shivering agent selectedfrom the group consisting of α2-adrenoreceptor agonists, non-opiodanalgesic monoamine uptake inhibitors and neuropeptides is to beadministered, which is intended to be a dosage sufficient to reduce oreliminate shivering in the patient being treated. The actual dosageamount will vary depending upon the patient's age and weight, along withthe dosage form and α2-adrenoreceptor agonist, non-opiod analgesicmonoamine uptake inhibitor or neuropeptide selected. Generally a typicaldosage will be within the range of about 0.5 to 10 mg/kg of body weight,preferably about 0.5 to 2.0 mg/kg of body weight, and most preferablyabout 0.5 to 1.0 mg/kg of body weight. It is believed that 0.1 mg to 5.0g of the anti-shivering agent will provide a therapeutic effect in themethods of the invention.

The preferred dosage will be dependent upon the time period during whichthe patient's body temperature is being reduced (either from a feveredstate to normothermic or from normothermic to a hypothermic state),along with the actual drop in patient temperature that will beexperienced during this procedure. Accordingly, for the methods of theinstant invention, the amount of anti-shivering agent administeredshould be sufficient to reduce shivering while the body temperature isbeing reduced and maintained at the lower temperature, which may be24–72 hours.

It is important to note that the amount of anti-shivering agent requiredfor maintaining a patient at a predetermined temperature withoutshivering may be different than the amount required when the patient'stemperature is being lowered to reach a predetermined temperature. Forexample, a patient may require a different dose of an anti-shiveringagent, generally more, to prevent shivering during active cooling thanthe dose needed to prevent shivering while being maintained at thetarget temperature. For this reason, it may be desirable to monitor thelevel of patient shivering, as shown in FIG. 23, so that theadministration of the anti-shivering agent can be adjusted accordingly.Another factor to consider when selecting a dosage is the rate at whichthe temperature of the patient is being changed, i.e. the rate ofcooling, since this may affect the shivering response and thus the doseof anti-shivering agent that is appropriate. Likewise, the shiveringresponse may be different at different temperatures below the shiveringthreshold. For example, a patient might shiver more vigorously at 34° C.than at 32° C. Additionally, of course, individuals will vary widely intheir shivering thresholds, the vigor of their shivering response, andtheir sensitivity to the agent. The various α2-adrenoreceptor agonists,non-opiod analgesic monoamine uptake inhibitors and neuropeptide mayalso vary in strength depending on their individual purity andpreparation. For all these reasons, dosage recommendations herein aremerely suggestive and by no means comprehensive or restrictive.

Fosphenytoin has sometimes been administered as an anti-convulsant drug.As such an appropriate dosage was 20 mg PE/Kg. (75 mg/mL of fosphenytoinsodium is equivalent to 50 mg/mL of the active metabolite, phenytoinsodium. As is common in the art, dosage and rate of administration areusually expressed in the physical equivalent (PE) of the activeingredient.) However, one such dose was found not to be effective ateliminating shivering, and two doses were administered back to back andwere found to be effective. Thus the effective anti-shivering dosage isabout double the amount effective as an anti-convuslant dosage. Thetiming and means of administration are set forth in the followingsections.

Route of Administration of Anti-shivering Agents

There are numerous routes and formulations by which theα2-adrenoreceptor agonist, non-opiod analgesic monoamine uptakeinhibitor or neuropeptide can be administered to the patient undergoingthe hypothermia inducing procedures described herein. For example, theanti-shivering agent can be administered either alone or in combinationwith other pharmaceutically acceptable excipients, including solid,semi-solid, liquid or aerosol dosage forms, such as, for example,tablets, capsules, powders, liquids, injectables, suspensions,suppositories, aerosols or the like. The anti-shivering agent can alsobe administered in sustained or controlled release dosage forms,including depot injections, osmotic pumps, pills, transdermal (includingelectrotransport) patches, and the like, for the prolongedadministration of the anti-shivering agent at a predetermined rate. Thecompositions will typically include a conventional pharmaceuticallyacceptable carrier or excipient and the anti-shivering agent or apharmaceutically acceptable salt thereof. In addition, the compositionmay include other medicinal agents, pharmaceutical agents, carriers,adjuvants, and so forth. Generally, depending on the intended mode ofadministration, the pharmaceutically acceptable composition will containabout 0.1–90.0% by weight, preferably about 0.5–50.0 wt %, of theanti-shivering agent or its salt, the remainder being suitablepharmaceutical excipients, carriers, etc. See, for example, “Remington'sPharmaceutical Sciences” (Mack Publishing Company, Pennsylvania, 18thEdition, 1990) and “Goodman & Gilman's the Pharmacological Basis ofTherapeutics”, (Goodman, et al., Eds., 9th edition, 1996) for extensivediscussions on the preparation and composition of various formulationssuitable for use in administering the anti-shivering agents describedherein.

The anti-shivering agent can be administered orally, transdermally,directly into the cerebrospinal fluid (e.g., intracereboventricualrly orintracisternally) or parenterally (intramuscularly or intravenously),with intramuscular or intravenous injection being the preferred routesof administration.

For oral administration, the compositions may take the form of asolution, suspension, tablet, capsule, powder, sustained releaseformulation, and the like. A typical pharmaceutically acceptablecomposition is formed by the incorporation of any of the normallyemployed excipients, such as, for example, a diluent (lactose, sucrose,glucose, dicalcium phosphate), lubricant (magnesium stearate),disintegrant (croscarmellose sodium), binder (starch, gum acacia,polyvinylpyrrolidone, gelatin, cellulose, cellulose derivatives),mannitol, povidone, sodium saccharine, talcum, magnesium carbonate, andthe like. Such compositions take the form of solutions, suspensions,tablets, dispersible tablets, pills, capsules, powders, sustainedrelease formulations and the like.

Liquid pharmaceutically administrable compositions can, for example, beprepared by dissolving or dispersing an anti-shivering agent andoptional pharmaceutical adjuvants in a carrier, such as, for example,water, saline, aqueous dextrose, glycerol, glycols, ethanol, and thelike, to thereby form a solution or suspension. If desired, thepharmaceutical composition may also contain minor amounts of nontoxicauxiliary substances such as wetting agents, suspending agents,emulsifying agents, or solubilizing agents, pH buffering agents and thelike, for example, sodium acetate, sodium citrate, cyclodextrinederivatives, polyoxyethylene, sorbitan monolaurate or stearate,triethanolamine oleate, etc. Liquid or semi-solid oral formulations canalso be prepared by dissolving or dispersing the anti-shivering agent orits salt in vegetable oils, glycols, triglycerides, propylene glycolesters (e.g. propylene carbonate) and the like, and encapsulating thesesolutions or suspensions in hard or soft gelatin capsule shells toprovide a solid dosage form.

Formulations for parenteral injection can be prepared in conventionalforms, either as liquid solutions or suspensions, solid forms suitablefor solution or suspension in liquid prior to injection, or asemulsions. Formulations of 0.1 to 10 wt % anti-shivering agent insolution are acceptable, with 2.5 wt % being typical.

Fosphenytoin may be administered intravenously at a rate of about 150MgPE/min. As mentioned above, about 75 mg of fosphenotoin sodium isequivalent to 50 mg of phenotoin so this translates to a rate ofadministration of about 225 mg/min of fosphenotoin.

Timing of Administration of the Anti-shivering Agent

When inducing hypothermia, it is preferred to have therapeutic levels ofthe α2-adrenoreceptor agonist, non-opiod analgesic monoamine uptakeinhibitor or neuropeptide anti-shivering agent in the blood stream ormaintenance of the skin temperature already established by warming theskin, while the heat exchange device is being used to lower thepatient's core temperature. Accordingly, the preferred methods of theinvention contemplate administration of the anti-shivering agent priorto initiation of the cooling step. When controlling the rate of heatingof an already hypothermic patient, or when maintaining hypothermia at astable temperature below the shivering threshold, it is also preferableto have therapeutic levels of the anti-shivering agent in the bloodstream or the skin temperature already being maintained by warming theskin. This can be accomplished by administering a bolus dosage toachieve the desired therapeutic level of anti-shivering agent in theblood, which can then be subsequently maintained by periodic orcontinuous administering the anti-shivering agent. The anti-shiveringagent may be administered periodically at a larger dose, for exampleintramuscular, or can be administered continuously at a smaller dose,for example intravenously.

The anti-shivering agent may be administered prior to positioning theheat exchange device, before the cooling step commences, simultaneouswith the cooling step, which can commence at the time the device isinserted or applied externally to the patient or at the time that theheat exchange device is activated, or at a point in time subsequent tothe initiation of the cooling step. Yet another embodiment contemplatescontinuing to administer the anti-shivering agent for some time afterthe heat exchange device has ceased to operate. As noted above, a singleone-time dosage of agent, several periodic dosages of agent administeredat set time intervals, continuous administration of agent, or acombination of these are also contemplated. The actual timing ofadministration of the anti-shivering agent is best illustrated in FIG.23, which shows the numerous points at which the anti-shivering agentcan be administered, either sequentially or simultaneously with theother steps in the methods of the invention.

Heat Exchange Devices

The heat exchange device itself is preferably a catheter which comprisesat least one fluid lumen through which a thermal exchange fluid may becirculated, a heat exchanger and a working lumen extending from outsidethe patient through at least part of the catheter that is inserted intothe patient. An example of such a catheter may be an elongate catheterhaving a proximal end and a distal end, where the entire length of saidflexible catheter is defined as the distance from its proximal end toits distal end, and comprising at least one fluid lumen through which athermal exchange fluid may be circulated, a heat exchanger with heatexchange fins located at a first location on the catheter, and a workinglumen extending from outside the patient through at least part of thecatheter that is inserted into the patient.

The heat exchanger operates to exchange heat between blood which flowsin heat exchanging proximity to the heat exchanger and a thermalexchange fluid which is circulated through the catheter. The firstlocation at which the heat exchanger is located may constitute less thanthe entire length of the catheter, and is typically at or near thedistal end of the catheter. The heat exchanger may specifically comprisea balloon or other structure through which the thermal exchange fluidmay circulate, and the heat exchange fins may be a plurality of lobes ofthe balloon or other surface area increasing projections such asoutwardly extending protuberances, ribs, filaments of a multi-filamentdevice, curved or undulating surfaces, etc., that enhance the efficiencywith which heat exchange occurs.

The invention also contemplates a means for controlling the heatexchange device so that a predetermined temperature is established andmaintained. For example, a control system can monitor body temperatureand the device is then controlled in response to the body temperature.In this manner, the device can be modulated or shut off when thepatient's body or target region reaches a pre-selected temperature, andsimilarly, can be modulated, for example turned on, when the temperaturedeviates from the pre-selected temperature.

A significantly more sophisticated and automatic control overtemperature regulation is possible. Examples of such control systems areshown in FIG. 24 and FIG. 25. In the control system, feedback from thepatient's body is obtained by one or more temperature sensors attachedto the patient. Examples include an esophageal temperature probe 222, atympanic temperature probe 224, a skin temperature probe 226, a rectaltemperature probe 228, or other appropriate sensors as is well known inthe art. These probes generate signals that represent the temperaturesensed and transmit those signals over a plurality of wires 230 to acontrol unit 232, one embodiment of which is illustrated in FIG. 25. Thecontrol unit receives the temperature signals and controls the heatexchange region 234 of the heat exchange catheter 236 in responsethereto.

FIG. 25 illustrates another embodiment of a control unit 250 may includea programmable computer 238, a thermoelectric heater/cooler 240, asupply of heat exchange fluid 242, and a pump 244. The pump may pump theheat exchange fluid through the supply source, for example, a bag 242over the thermoelectric heater/cooler to alter the temperature in thefluid. The fluid may be pumped from an inlet tube 246 received from theheat exchange catheter, through the bag and back to the heat exchangecatheter through the outlet tube 248. In response to the temperaturesensed, the controller may control the pump rate, or may control thetemperature of the thermoelectric heater/cooler.

In one embodiment, the control unit is programmed to control the heatexchange catheter to reach and maintain a target temperature. The supplyof heat exchange fluid is a closed loop of heat exchange fluidcirculating through the catheter inside the patient and external of thepatient through the bag of fluid positioned adjacent the thermoelectricheater/cooler. As the sensed temperature of the patient approaches thetarget temperature, the control unit may adjust the temperature of thethermoelectric heater/cooler to approach the target temperature. Forexample, if the computer was programmed to control the patient'stemperature at 32° C., the thermoelectric cooler might originally be ata temperature of near 0° C., and thus the temperature of the heatexchange fluid flowing within the balloon would be about 0° C. However,as the temperature of the patient fell and began to approach 32° C., thecontrol unit would act to increase the temperature of the thermoelectricheater/cooler (by altering the current flowing therethrough, forexample) so that it began to warm toward 32° C. It has been found that atemperature of the heat exchange fluid of about 30° C. will removeapproximately the amount of heat that a body at rest at 32° C.generates, so as the body temperature reaches the target temperature of32° C., the control unit will gradually control the thermoelectricheater/cooler to level off at a constant temperature of 30° C.

Similarly, the control unit may regulate the rate of temperature change.A rate of change of patient temperature may be programmed into thecomputer of the controller. If the sensed temperature of the patient ischanging more rapidly or more slowly than the programmed rate, thetemperature of the heat exchange fluid may be controlled by controllingthe thermoelectric heater/cooler and thus removing or adding heatthrough the heat exchange catheter to the blood of the patient inappropriate amounts to control the rate of temperature change in thepatient.

It may be readily seen that many variations on this control unit arepossible without departing from the invention. For example, the controlunit may receive signals from one, two or more temperature sensors,which would be included in the control system. Sensors of otherparameters than body temperature, such as pulse rate or blood pressureor the like, are within the contemplation of the invention, and may alsobe included in the control system. Likewise, the target temperature isonly one end point that may be desirable with the controller; the targetmay be some other bodily condition such as blood pressure, EEGcondition, and the like. Also the nature of the response of the controlunit which serves to control the heat exchanger may vary. It may be asimple as an on/off response. It may vary the rate of pumping, thetemperature of the thermoelectric plate, or any other suitable variableto control the heat exchanger.

If the anti-convulsant drug phenytoin is administered as theanti-shivering agent, it should be administered at least 15 minutesbefore the anti-shivering effect is desired. For example, if thepatient's temperature is normothermic, and it is estimated that theendovascular cooling system may take 15 minutes to cool the patient downto the shivering threshold, the fosphenytoin may be administeredsimultaneously with starting the cooling. As the procedure continues, ifthe anti-shivering effect is desired for an extended period, for examplemore than 4 hours, then additional parenteral administration of the drugmay be needed to maintain the necessary effective level, as long astoxic levels of the drug are avoided. The standard pharmaceuticalliterature gives the needed guidance regarding toxic level andcontraindications, and as mentioned above, about double the effectiveanti-convulsant dosage is effective as an anti-shivering agent.

Kits

Another aspect of the invention pertains to a kit for reducing thetemperature of a patient comprising (a) a heat exchange device and (b)an agent selected from the group consisting of α2-adrenoreceptoragonists, non-opiod analgesic monoamine uptake inhibitors andneuropeptides. The kit may contain instructions, as appropriate, both asto the operation of the device and the anti-shivering mechanism. The kitmay also include information pertaining to the storage and dosageinstructions for the agent, and so forth

For example, the kit may contain instructions for the proper insertionof the catheter into the vascular system as is well known in the medicalarts, for example by the Seldinger technique. The instructions may alsocontain a description of the proper use of the heat exchange cathetersystem, the proper target temperature for the patient, and if the kitcontains a control unit, the appropriate ramp rates for heating andcooling the patient, as well as specific recommendations for the use ofthe α2-adrenoreceptor agonist, non-opiod analgesic monoamine uptakeinhibitor or neuropeptide. The kit may or may not contain theanti-shivering, but may contain a description of the preferredα2-adrenoreceptor agonist, non-opiod analgesic monoamine uptakeinhibitor or neuropeptide, for example a preferred α2-adrenoreceptoragonist, non-opiod analgesic monoamine uptake inhibitor or neuropeptideselected from those set out above, and suggestions as to dosage andmethods of administration and the like. The duration of administrationof cooling and use of the anti-shivering mechanism may also be set out.

In one embodiment of the kit, the heat exchange device is a catheter. Asuitable catheter is an elongate catheter having a proximal end and adistal end, the entire length of the catheter being defined as thedistance from its proximal end to its distal end, and comprises (i) atleast one fluid lumen through which a thermal exchange fluid may becirculated; (ii) a heat exchanger with heat exchange fins located at afirst location on the catheter; and (iii) a working lumen extending fromoutside the patient through at least part of the catheter that isinserted into the patient.

The kit can optionally include a control system that monitors bodyconditions, for example by measuring temperature, and controls the heatexchange device in response to the body conditions being monitored, suchas turning off the device when the patient's body or target regionreaches a pre-selected temperature, or reactivating the device when thetemperature deviates from the pre-selected temperature. In addition, thekit may also comprise a second heat exchange device. This second devicemay serve to compliment the temperature lowering ability of the firstdevice, i.e., the second device may also serve to lower the temperatureof the body or portion thereof. Alternately, the second device may serveto increase the temperature of the patient's body or body portion. Thisis useful to provide heat in the event that the method of the inventionresults in a lower temperature than is desired, or if it is desired toconclude the therapy and raise the patient's temperature tonormothermic.

These and other methods of the invention are readily understood inreferences to the figures described below. One embodiment of the heatexchange device suited for use in the methods of the invention isillustrated in FIG. 1, which shows the distal end 2 of a heat exchangedevice 4, which has been inserted through the patient's skin into ablood vessel 6. Blood flow through the vessel is indicated by a set offlow arrows. Preferably, the device is inserted into a relatively largeblood vessel, e.g., the inferior or superior vena cava, a femoral arteryor vein, a jugular artery or vein, or the aorta. Use of these vessels isadvantageous in that they are readily accessible, provide safe andconvenient insertion sites, and have relatively large volumes of bloodflowing through them. In general, large blood flow rates facilitate moreefficient heat transfer between the catheter and the blood. For example,the jugular vein may have a diameter of about 22 French, or a bit morethan 7 mm, where 1 French is 0.013 inches or 0.33 mm. A heat exchangedevice suitable for insertion into a vessel of this size can be madequite large relative to devices intended for insertion into smallervessels in the vascular system.

A particularly well suited heat exchange device is a catheter.Atherectomy or balloon angioplasty catheters, used to clear blockagesfrom the coronary artery and similar vessels, commonly have externaldiameters in the range between 2 to 8 French. In contrast, it isanticipated that a catheter useful in the methods of the instantinvention will typically have an external diameter of about 9 French,although this dimension may obviously be varied a great deal withoutdeparting from the basic principles of the claimed invention. It isdesirable that the catheter or other heat exchange device be smallenough so that the puncture site can be entered using the percutaneousSeldinger technique, a technique well known to medical practitioners.Other techniques for inserting devices into the above mentioned bloodvessels are also well known among medical personnel.

Although a small diameter is chosen for the heat exchange device, thisdiameter is based upon the pre-insertion size, and is aimed at avoidingor minimizing vessel trauma. However, after the device is inserted inthe vessel, its distal end can be expanded to any size so long as bloodflow is not unduly impeded. Additionally, the femoral artery and veinand the jugular vein are all relatively long and straight blood vessels.This will allow for the convenient insertion of a device having atemperature controlled region of considerable length. This is of courseadvantageous in that more heat may be exchanged at a given temperaturefor a device of a given diameter if the length of the heat transferregion is increased. Although the method of the present invention willprobably be most commonly employed in a hospital, the procedure need notbe performed in an operating room. The method and apparatus are sosimple that the device may be inserted and treatment to lower thepatient's temperature and reduce shivering may begin even in anambulance or in the field.

In general, the distal end 2 of the device may be cooled and maintainedat a temperature below the patient's body temperature. Blood flowingthrough the vessel will therefore be cooled, and will then be circulatedrapidly throughout the patient's circulatory system. The beneficialeffect of cooling the patient's blood in the vicinity of the device willthereby be spread very quickly throughout the entire body of thepatient.

The device depicted in FIG. 1. can utilize a variety of cooling methodsand can have numerous configurations that maximize its heat exchangingcapability. A particularly well suited heat exchange device is acatheter, several configurations of which are described in detail inGinsburg, U.S. Pat. No. 5,486,208 and Ginsburg, WO 98/26831, thedisclosures of which are incorporated herein by reference. For examplethe catheter can have a thermally conductive shaft running the length ofthe catheter body, made of a metal or other material having a highthermal conductivity. By cooling the proximal end of the shaft with anexternal cooling apparatus, heat will be caused to flow either into thedistal end of the shaft. Another cooling mechanism is provided by acatheter having two lumens running through it. Fluid flows from theproximal end of the catheter through in-flow lumen, through a heattransfer region, and back out through an out-flow lumen. By supplyingcooled fluid through the inflow lumen, heat may be transferred from thepatient's blood stream. Other embodiments and modifications for heattransfer other than by use of a heat exchanging fluid, e.g., resistance,including radio frequency, will occur to those skilled in the art.

The heat exchange devices useful in the methods of the invention arepreferably designed to optimize the rate of heat transfer between thedevice and the body, tissue or fluid, for example with blood flowingthrough the vessel. While a large surface area is desirable in order toincreasing the effective heat transfer, care must be taken so that thedevice does not unduly restrict blood flow through the vessel. Thedevice can be fitted with a plurality of protrusions to maximize theheat transfer surface area, such as heat transfer vanes, radial fins orlongitudinal fins, or a multi-lobed balloon surface, collectivelyreferred to as heat exchange fins. In addition, the heat transfer regionof the device can be in the form of an expandable balloon, where theballoon remains inflated by, for example, the pressure difference in afluid flows through an inflow and outflow lumen.

It is estimated that heat exchange device whose surface temperature iscontrolled between about 1 to 15° C. and may provide a body core coolingrate of approximately 6 to 8° C. per hour in a patient of typical size,for example 115 pounds to 195 pounds and having approximately normalbody temperature (37° C.). This estimate is highly dependent on a numberof factors including the rate of blood flow through the vessel, theinitial body temperature of the patient, the external surface area ofthe device through which heat is transferred, etc. The actual rateachieved may vary substantially from the above estimate. A more helpfulestimation of temperature control of the patient's body may be thewattage of energy [heat] removed from the body. At normal blood flowsover a catheter as described, as many as 300 watts of energy may beremoved from the blood. At rest, the human body generates about 100watts, but shivering may increase this amount to as much as five-fold.The ability to cool the body or control the body's temperature is thusgreatly enhanced by the administration of anti-shivering agents whileemploying the cooling catheter. Other design considerations include asensitive temperature sensor (see for example, FIG. 23) to closelymonitor the temperature of the distal end of the device. While careshould be taken to avoid freezing the tissue or fluid or inducing shockto the patient, this is rarely a concern. Since blood is essentiallywater containing a number of suspended and dissolved substances, itsfreezing point is somewhat below 0° C.

As may be readily appreciated, the rate of temperature alteration of thepatient is greatly dependent on the amount of heat being removed fromthe blood. This in turn is greatly dependent on the difference intemperature between the blood and the surface of the heat exchangedevice (ΔT). When it is desirable to rapidly cool the patient, thetemperature of the device will be as cold as possible, for example bycooling a heat exchange fluid to almost 0° C., whereas when the operatorwants the patient's temperature to remain constant, for example after astate of hypothermia has been reached, only the amount of heat generatedby the body in excess of that which is normally lost to the environmentneeds to be removed. Thus it may be that the temperature of the balloonsurface may be maintained near 0° C. during cooling, and as the bodyreaches the required hypothermic level, the temperature of the heatexchange surface may be maintained just a few degrees below bodytemperature, for example at about 30° C. once the hypothermic state of32° C. has been reached.

In heating, it is conservatively accepted that a temperature of a devicein contact with the blood may be 42° C. without causing injury to theblood. The ΔT in warming then will generally be less than when the heatexchanger is cooling the blood. If a carefully controlled rate ofwarming is desired, it will be readily appreciated that a large amountof metabolic heat generated by the body by shivering may overwhelm thesystem's ability to precisely control the rate of warming. Thereforeeven when warming a hypothermic patient, control of shivering isimportant.

Some preferred configurations of heat exchange devices are illustratedin the accompanying figures. In FIG. 2, a heat exchange balloon catheter10 with a finned balloon portion 12 may be positioned within at least aportion of the descending aorta 14 and a blood vessel 16 conductingblood flow to the brain region. The balloon portion 12 is typicallyformed of material that is sufficiently thin to promote effectivethermal transfer between heat exchange fluid within the balloon andblood flowing within heat exchange proximity of the balloon, but whichis not excessively elastic to expand and unintentionally obstruct afluid passageway or blood vessel 16. A particularly suitable material isa thin, strong but relatively inelastic material such as PET(polyethylene terephthalate), which will allow for a predictable balloonconfiguration with adequate heat exchange properties. The catheter shaft18 of the thermal catheter 10 may be placed in a desired locationrelative to a selected body region or artery 16 by conventionaltechniques such as guiding catheters or steerable wire over-the-wiretechnique as known to those of ordinary skill in the field. The balloonportion 12 of the catheter 10 may support the closed-loop circulation ofa heat transfer fluid within the catheter and balloon as described inthe example set forth below. The increased surface area of the inflatedballoon may provide effective heat transfer within a body region bythermal conduction, and the configuration of the balloon may furtherpermit continued blood flow without substantial disruption by creatingchannels exterior of the balloon surface when the balloon is expanded.

FIG. 3 illustrates a heat exchange balloon 12 mounted on a shaft 18, theballoon being defined by a longitudinal axis and a plurality of heattransfer fins 20, 22, 24 and 26 projecting radially outward from thelongitudinal axis of the catheter shaft. The heat transfer fins may beformed, for example, as the lobes of a multi-lobed, collapsible balloon.The shaft 18 is generally round and in this embodiment includes aworking lumen 28 running through the shaft and open at the distal end ofthe catheter. Although in a preferred method, the anti-shivering agentis administered by intramuscular or intravenous injection, it may alsobe administered through the central, or working lumen

In one embodiment of the invention, the working lumen is used for theinjection of the anti-shivering agent. The working lumen can also serveother functions. For example, along with being provided in combinationwith an anti-shivering agent, the catheter device may further beprovided in combination with a device (such as a guide wire, orembolectomy catheter) or other medicament (such as a thrombolytic agent,a barbiturate, an anticoagulant, a neuroprotectant, an anticonvulsantagent, an oxygenated perfusate, a vasodilator, an agent which preventsvasospasm, an agent to prevent platelet activation, and an agent todeter the adhesion of platelets), all of which can be insertion throughthe working lumen. In addition, the working lumen may be used for theinjection of fluoroscopic dye, for the receipt of a guide wire, or as aguiding catheter for various diagnostic or therapeutic devicesincluding, for example, an angioplasty catheter, an embolectomycatheter, an occlusion member delivering catheter, an embolizationmember delivering catheter, an electro-cautery device, or amicrocatheter. As may be appreciated, the use of the lumen for onefunction does not prevent its subsequent use for another, so it may beused sequentially for several or even all of the uses described here.

The shaft exterior of the central lumen is shown in FIG. 4 and FIG. 6 asbeing divided by a web 30 into two channels, an inlet channel 32 and anoutlet channel 34. The shaft has inlet orifices 36, 38, 40 (shown inFIG. 3) communicating between the inlet channel and the interior of theballoon at the distal portion of the balloon. The shaft also has outletorifices 42, 44, 46 communicating between the interior of the balloonand the outlet channel. A plug 48 is inserted in the outlet channelbetween the inlet and the outlet orifices.

The balloon 12 may be made of, for example, a single sheet ofcollapsible thin plastic material 50, as shown in FIG. 5 sufficientlythin to allow for effective thermal exchange between a heat exchangefluid on the interior of the balloon and blood flowing over the exteriorof the balloon. Tacking the material to the shaft as shown at 52 mayform lobes of the balloon. Tacking the sheet of plastic to itself inappropriate locations as shown at 54 and 56 may further shape the lobes.The lobed shape of the balloon surface provides a significant surfacearea for heat exchange while also providing for continued flow past theballoon through the space between the lobes of the balloon.

In operation, heat exchange fluid (not shown) is pumped under pressureinto the inlet channel 32. Suitable heat exchange fluids include, by wayof illustration and not limitation, sterile saline or otherbiocompatible fluid with appropriate heat transfer characteristics. Theheat exchange fluid flows down the inlet channel until it reaches theinlet orifices 36, 38, 40 at the distal end of the balloon. The fluidflows from the inlet channel into the interior of the balloon. It thenflows in a proximal direction through the interior of the balloon untilit reaches the outlet orifices 42, 44, 46 at the proximal end of theballoon. The heat exchange fluid then flows from the interior of theballoon through the outlet orifices and into the outlet channel 34 whereit then flows back down the shaft and out of the body. In this manner,the heat exchange fluid absorbs heat from the blood flowing in heattransfer proximity to the balloon.

An alternative construction to the heat exchange balloon is shown inFIG. 7 wherein the heat exchange region is formed using a series ofthree collapsible balloon lobes 60, 62, 64 located around a centralcollapsible lumen 66. A proximal shaft 68 is formed having two channels,an inlet channel 70 and an outlet channel 72. The interior of the shaftis divided into two lumens by webs 74 and 76, as shown in FIG. 12, butthe lumens do not occupy equal portions of the interior of the shaft.The inlet channel occupies about ⅓ of the circumference of the interior;the outlet channel occupies about ⅔ of the circumference of the interiorfor reasons that will be explained below.

At the heat exchange region of the catheter, a transition 78 is formedbetween the shaft 68 and the tube 80 forming the central collapsiblelumen 66. The outlet channel is plugged 82, as shown in FIG. 10, thetube 80 is affixed over the shaft 68 by, for example gluing, at thetransition 78, and the shaft ends with the tube (not shown). In thisway, as shown in FIG. 9, the inlet channel in this portion of thecatheter occupies the entire circumference of the shaft. At the distalend of the balloon, shown in FIG. 8, inlet orifices 84, 86, 88 areformed between the inlet channel and the three collapsible balloons. Atthe proximal end of the heat exchange region, shown in FIG. 11, outletorifices 90, 92, 94 are formed between the interior of each balloon andthe outlet channel in the shaft. The configuration of the outlet channelis such that communication with the interior of each of the threeballoons is possible.

In operation, heat exchange fluid flows down the inlet channel in theshaft 70, continues down lumen 66 to the distal end of the heat exchangeregion, exit the lumen through the inlet orifices 84, 86, 88 to theinterior lumens of the balloon lobes 96, 98, 100, travel back down eachof the three balloons and re-enter the shaft through the outlet orifices90, 92, 94 and then down the outlet channel 72 toward the proximal endof the catheter. In this way heat exchange fluid may be circulatedthrough the three balloons to remove heat from the blood flowing in heattransfer proximity to the balloons. The material from which the balloonsare made is made of a material that will permit significant thermalexchange between the heat exchange fluid on the interior of the balloonand the body fluid such as blood flowing in heat exchange proximity tothe surface of the balloon. A particularly suitable material is verythin plastic material, which may also be made strong enough to withstandthe pressure necessary for adequate flow of the heat exchange fluid.

FIG. 13 illustrates another heat exchange catheter 102 suitable for usein the method of this invention. The catheter 102 is constructed byattaching a balloon 104 having multiple lumens, over an inner shaftmember 106 in the manner described below. The assembled catheter 102(FIG. 13) has a four-lumen thin-walled balloon 104 (FIG. 15) which isattached over an inner shaft 106 (FIG. 14).

The cross-sectional view of the four-lumen balloon taken along line16—16 of FIG. 15 is shown in FIG. 16. The four-lumen thin-walled balloon104 has three outer lumens 108, 110 and 112, which are wound around aninner lumen 114 in a helical pattern. All four lumens are thin walledballoons and each outer lumen shares a common thin wall segment (116,118, 120) with the inner lumen 114. The balloon is approximatelytwenty-five centimeters long and when installed, both the proximal end122 and the distal end 124 are sealed around the shaft 106 in a fluidtight seal.

The shaft 106 is attached to a hub 126 at its proximal end. Thecross-sectional view of the proximal shaft at line 17—17 in FIG. 14 isshown at FIG. 17. The interior configuration of the shaft has threelumens: a guide wire lumen 128, an inflow lumen 130 and an outflow lumen132. It is understood however, the lumens 130 and 132 are referred to asinflow and outflow for illustrative purposes only. One of skill in theart may readily appreciate that lumen 132 may be used as the inflowlumen and lumen 130 may be used as the outflow lumen if the flow of theheat exchange fluid is reversed.

At the hub 126, the guide wire lumen 128 communicates with a guide wireport 134, the inflow lumen 130 is in fluid communication with an inflowport 136, and the outflow lumen 132 is in communication with an outflowport 138. Attached at the hub 126 and surrounding a portion of shaft 106is a length of strain relief tubing 140 which may be, for example,shrink tubing.

Between the strain relief tubing 140 and the proximal end 122 of theballoon, the shaft 106 is at the extruded outer diameter of about 0.118inches. The internal configuration is as shown in FIG. 17. Immediatelyproximal of the balloon attachment at its proximal end 22, the shaft hasa necked down section 142. The outer diameter of the shaft is reduced toabout 0.10 to 0.11 inches, but the internal configuration of the lumensis maintained. Compare, for example, the shaft cross-section shown inFIG. 17 with the cross-section shown in FIG. 18 or the shaftcross-section shown in FIG. 20. This length of reduced diameter shaftremains at approximately constant diameter between the first necked downsection 142 and a second necked down section 144.

Immediately distal of the necked down section 142, a proximal balloonmarker band 146 is attached around the shaft. The marker band 146 is aradiopaque material such as a platinum band or radiopaque paint, and isuseful for locating the proximal end of the balloon by means offluoroscopy while the catheter is within the body of the patient.

At the marker band 146, the distal end of all four lobes of the balloon(108, 110, 112, 114) at 122 are fastened to the inner member 122. Thismay be accomplished by folding the balloon down around the shaft,placing a sleeve, for example a short length of tubing, over the balloonand inserting adhesive, for example by wicking the adhesive around theentire inner circumference of the sleeve. This simultaneously fastensthe balloon down around the shaft, and creates a fluid tight seal at theproximal end of the balloon.

Distal of this seal, under the balloon, a window 148 is cut through thewall of the outflow lumen in the shaft. Juxtaposed to that window, aplurality of slits 150 are cut into the wall of the outer balloon lumen,as shown in the cross-sectional view of FIG. 18 and the view in FIG. 19.Because the outer lumens are twined about the inner lumen in a helicalfashion, each of the outer tubes passes over the outflow lumen of theinner shaft member at a slightly different location along the length ofthe inner shaft, and where each of the other two outer lumens pass overthe outflow lumen of the shaft, other windows (152, 154) are cut intothe outflow lumen and a plurality of slits (156, 158) are cut into theouter lumen to fluidly connect the proximal portion of that outer lumento the outflow lumen of the shaft. See, for example, the section of FIG.13 immediately distal of line 18—18. In this way the proximal portion ofeach outer lumen (108, 110, 112) is fluidly connected to the outflowlumen of the shaft.

Distal of the windows in the outflow lumen, the inner lumen 114 of thefour-lumen balloon is sealed around the shaft in a fluid tight seal. Theoutflow lumen 132 is plugged 160, and the wall to the inflow lumen isremoved, as shown in FIG. 20. This may be accomplished by the neckeddown section 144 to seal the outflow lumen shut (plug 160), removing thewall 162 of the inflow lumen 130, and affixing the wall of the innerlumen of the balloon around the entire outside 164 of the shaft withadhesive. The adhesive will also act as a plug to prevent the portion ofthe inner lumen proximal of the plug from being in fluid communicationwith the inner member distal of the plug.

Just distal of the necked down section 144, the guide wire lumen 128 ofthe shaft may be terminated and joined to a guide wire tube 166. Thetube 166 then continues to the distal end of the catheter. The inflowlumen 130 is open into the inner lumen of the four-lobed balloon andthus in fluid communication with that lumen.

The distal end 124 of the balloon 104 including all four lumens of theballoon is sealed down around the guide wire tube 166 in a mannersimilar to the way the balloon is sealed at the proximal end around theshaft. This seals all four lumens of the balloon in a fluid tight seal.Just proximal of the seal, a plurality of slits 168 are cut into thecommon wall between each of the three outer lumens 108, 110, 112, of theballoon and the inner lumen 144 so that each of the outer lumens is influid communication with the inner lumen, as is shown in FIG. 21 and thecross-sectional view of FIG. 22.

Just distal of the balloon, near the distal seal, a distal marker band170 is placed around the inner shaft. A flexible length of tube 172 maybe joined onto the distal end of the guide wire tube 166 to provide aflexible tip to the catheter. The distal end 174 of the flexible tube172 is open so that a guide wire may exit the tip. Medicine orradiographic fluid may also be injected distal of the catheter throughthe guide wire lumen.

In use, the catheter 102 is inserted into the body of a patient so thatthe balloon is within a blood vessel. Heat exchange fluid is circulatedinto the inflow port 136, travels down the inflow lumen 130 and into theinner lumen 114 at the wall 162 at the end of the inflow lumen. The heatexchange fluid travels to the distal end of the inner lumen and throughthe slits 168 between the inner lumen 114 and the outer lumens 108, 110and 112.

The heat exchange fluid then travels back through the three outer lumensof the balloon to the proximal end of the balloon. The outer lumens arewound in a helical pattern around the inner lumen. At some point alongthe proximal portion of the shaft, each outer lumen is located over theportion of the shaft having a window (154, 152, 148) to the outflowlumen and the outer balloon lumens have a plurality of slits (158, 156,150) that are aligned with the windows. The heat transfer fluid passesthrough the slits (158, 156, 150) through the windows (154, 152, 148)and into the outflow lumen 132. From there it is circulated out of thecatheter through the outflow port 138.

Counter-current circulation between the blood and the heat exchangefluid is highly desirable for efficient heat exchange between the bloodand the heat exchange fluid. Thus if the balloon is positioned in avessel where the blood flow is in the direction from the proximal towardthe distal end of the catheter, for example if it were placed from aninsertion point in the femoral vein into the ascending vena cava, it isdesirable to have the heat exchange fluid in the outer balloon lumensflowing in the direction from the distal end toward the proximal end ofthe catheter, as is the arrangement describe above. It is to be readilyappreciated, however, that if the balloon were placed so that the bloodwas flowing along the catheter in the direction from distal to proximal,for example if the catheter was placed into the ascending vena cava froman insertion point in the jugular vein, it would be desirable to havethe heat exchange fluid circulate in the outer balloon lumens from theproximal end to the distal end. This could be accomplished by merelyreversing which port is used for inflow direction and which for outflow.

In use, a physician may employ the method of the invention to place apatient in a hypothermic state. By use of the Seldginer technique, thephysician may insert a heat exchange catheter having a heat exchangeballoon into the femoral vein of the patient. The catheter is advanceduntil the heat exchange balloon is located in the inferior vena cava.The physician then utilizes the heat exchange system to circulate coldsaline through the heat exchange balloon, which removes heat from theblood flowing past the heat exchange balloon. The physician continues toutilize the heat exchange system for a sufficient length of time toreduce the temperature of the patient.

Simultaneously the physician administers an α2-adrenoreceptor agonist,non-opiod analgesic monoamine uptake inhibitor or neuropeptide in themanner and at the dosage/duration as described above. The physician mayadminister a bolus amount of the anti-shivering agent and subsequentmaintenance amounts of the agent, or may administer the agent in anyother effective manner. In any event, when the patient's temperaturefalls below the shivering threshold, the level of anti-shivering agentin the patient will be sufficient to reduce shivering. This in turnmakes the reduction in temperature by the heat exchange system moreeffective, and reduces the discomfort and other adverse effects ofshivering.

When the patient has reached the target temperature below the shiveringthreshold, the level of anti-shivering agent is maintained at aneffective level, so that the heat exchange system can maintain thepatient precisely at the target temperature. The system has one or morepatient temperature monitors that provide feedback to the control unitfor the system. Since the amount of metabolic heat generated by the bodyis reduced, and since the thermoregulatory mechanisms of the body arenot actively opposing the temperature control of the heat exchangesystem by shivering, the target temperature can more safely and moreprecisely maintain the patient at the target temperature.

When the physician wishes to re-warm a patient slowly from a hypothermiccondition below the shivering threshold, he or she may employ the methodof the invention to more precisely control the rate of warming. When thepatient has an effective level of anti-shivering agent so as to reduceshivering, the physician may activate the heat exchange system to beginin vivo core warming. The feedback from the patient temperature monitorsallows control of the heat exchange system to slowly warm the patient,or to slightly cool the blood of the patient if the patient's own bodyis functioning to warm the patient too fast. Because the very effectiveshivering mechanism is reduced or eliminated, the heat exchange systemhas sufficient power and precision to maintain the gentle rate ofwarming and prevent the body from re-warming too fast.

In each of the above examples, the anti-shivering agent can beadministered before the heat exchange begins, or may be administeredonly upon the initiation of shivering, or any appropriate manner.

Each of the patents, publications, and other published documentsmentioned or referred to in this specification is herein incorporated byreference in its entirety.

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the scope of the invention. Inaddition, many modifications may be made to adapt a particularsituation, material, composition of matter, process, process step orsteps, while remaining within the scope of the present invention.Accordingly, the scope of the invention should therefore be determinedwith reference to the appended claims, along with the full range ofequivalents to which those claims are entitled.

1. A method for changing the body temperature of a human or animalsubject while controlling subject shivering, comprising: A) providing aheat exchange catheter; B) positioning the heat exchange catheter in thevasculature of the subject; C) administering to the subject at least onedrug of a type selected from the group consisting of; serotoninagonists, dopamine antagonists, dopamine agonists, sedatives, hypnoticsand anxiolytics, said at least one drug being administered at a dose andby a route of administration that is effective to deter shivering duringperformance of the method; and D) using the heat exchange catheter totransfer heat from blood flowing through the subject's vasculature.
 2. Amethod according to claim 1 wherein Step C comprises administering aserotonin antagonist selected from the group consisting of: serotonin 5HT1a agonists, buspirone; ipsapirone; 8-OH-DPAT and flesinoxan andpharmaceutically acceptable salts thereof.
 3. A method according toclaim 1 wherein Step C comprises administering a dopamine antagonistselected from the group consisting of: haloperidol, phenothiazines,chiorpromazine, triflupromazine, thioridazine, mesoridazine,piperacetazine, piperazine, fluphenazine, trifluoperazine,acetophenazine, carphenazine, fluphenazine, perphenazine,prochiorperazine, neuroleptic dopamine antagonists, tioxanthenes,chlorprothixene, thiothixene, diphenylbutylpiperidines, pimozide,penfluridol, dibenzoxazepines, loxapine, dibenzodiazepines, clozapine,benzamides, sulpiride, butyrophenones, haloperidol, dopamineb-hydroxylase blockers, disulfiram and pharmaceutically acceptable saltsthereof.
 4. A method according to claim 1 wherein Step C comprisesadministering a dopamine agonist selected from the group consisting of:amantadine, bromocriptine, piribidil, apomorphine, lisuride, pergolide,mesulergine and pharmaceutically acceptable salts thereof.
 5. A methodaccording to claim 1 wherein Step C comprises administering a sedative.6. A method according to claim 1 wherein Step C comprises administeringa hypnotic.
 7. A method according to claim 1 wherein Step C comprisesadministering an anxiolytic.
 8. A method according to claim 1 whereinthe method further comprises administering to the subject at least oneother drug of a type selected from the group consisting of; opioids,opioid agonists, opioid antagonists and opioid agonists/antagonists. 9.A method according to claim 8 wherein the other drug comprises morphine.10. A method according to claim 8 wherein the other drug comprises anopioid agonist-antagonist selected from the group consisting of:nalorphine; pentazocine; buprenorphine; butorphanol; nalbuphine;cyclazozine; dezozine; and nalorphone; and their pharmaceuticallyacceptable salts thereof.
 11. A method according to claim 8 wherein theother drug comprises an opioid agonist selected from the groupconsisting of; bremazocine, nalorphine, ketazocine and alkyl ketazocinessuch as ethylketazocine, tifluadom,trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide,(5a,7a,8B)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro(4,5)-dec-8-yl]benzeneacetamide, bremazocine hydrochloride, nalorphine hydrochloride,ketazocine salts including alkyl ketazocine methanesulfonates such asethyl ketazocine methanesulfonate,trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide methanesulfonate, and pharmaceutically acceptable saltsthereof.
 12. A method according to claim 1 wherein Step C is performedbefore Step D.
 13. A method according to claim 1 wherein the heatexchange catheter provided in Step A has a heat exchanger through whicha heat exchange fluid is circulated and wherein Step D comprisescirculating a heat exchange fluid through said heat exchanger.
 14. Amethod according to claim 13 wherein the heat exchange fluid iscirculated through the heat exchanger in a direction opposite thedirection in which blood flows past the heat exchanger.